Marx Anna-Friederike, Kallert Sandra M, Brunner Tobias M, Villegas José A, Geier Florian, Fixemer Jonas, Abreu-Mota Tiago, Reuther Peter, Bonilla Weldy V, Fadejeva Jelizaveta, Kreutzfeldt Mario, Wagner Ingrid, Aparicio-Domingo Patricia, Scarpellino Leo, Charmoy Mélanie, Utzschneider Daniel T, Hagedorn Claudia, Lu Min, Cornille Karen, Stauffer Karsten, Kreppel Florian, Merkler Doron, Zehn Dietmar, Held Werner, Luther Sanjiv A, Löhning Max, Pinschewer Daniel D
Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland.
Department of Biomedicine, Division of Experimental Virology, University of Basel, 4055 Basel, Switzerland.
Immunity. 2023 Apr 11;56(4):813-828.e10. doi: 10.1016/j.immuni.2023.01.029. Epub 2023 Feb 20.
T cell factor 1 (Tcf-1) expressing CD8 T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8 T cells (CD8SL) remain poorly defined. Studying CD8 T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8 T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8SL-promoting pathway in the context of chronic viral infection.
表达T细胞因子1（Tcf-1）的CD8 T细胞具有干细胞样的自我更新能力，使其成为抵抗慢性病毒感染和癌症免疫防御的关键。然而，促进这些干细胞样CD8 T细胞（CD8SL）形成和维持的信号仍不清楚。通过研究慢性病毒感染小鼠的CD8 T细胞分化，我们确定警报素白细胞介素-33（IL-33）对CD8SL的扩增、干细胞样功能以及病毒控制起着关键作用。缺乏IL-33受体（ST2）的CD8 T细胞表现出偏向性终末分化和Tcf-1的过早丧失。通过阻断I型干扰素信号可恢复ST2缺陷型CD8SL反应，这表明IL-33可平衡IFN-I的作用，以控制慢性感染中CD8SL的形成。IL-33信号广泛增强了CD8SL中的染色质可及性，并决定了这些细胞的再扩增潜力。我们的研究确定IL-33-ST2轴是慢性病毒感染背景下促进CD8SL的重要途径。
